Mechanism of Hypoxia-Induced NF-κB
Mechanism of Hypoxia-Induced NF-κB
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DOI：
10.1128/mcb.00409-10
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发表时间：
2010-10-10
影响因子：
5.3
通讯作者：
Rocha, Sonia
中科院分区：
文献类型：
--
作者：
Culver, Carolyn;Sundqvist, Anders;Rocha, Sonia
NF-kappa B 激活是缺氧转录反应的关键组成部分。然而，在这些条件下控制其活性的潜在机制尚不清楚。在这里，我们报道，在缺氧条件下，I kappa B 激酶 (IKK) 活性是通过钙/钙调蛋白依赖性激酶 2 (CaMK2) 依赖性途径诱导的，这与 NF-kappa B 的其他常见诱导剂不同。这个过程仍然需要 IKK 和 IKK 激酶 TAK1，就像 NF-kappa B 炎症诱导剂一样，但 TAK1 相关蛋白 TAB1和TAB2不是必需的。缺氧后 IKK 复合体的激活需要 Ubc13，但不需要最近发现的 LUBAC（线性泛素链组装复合体）泛素缀合系统。与其他 NF-κ B 诱导剂的作用相反，IKK 介导的 Iκ B α 磷酸化不会导致其降解。我们证明这是 Sumo-2/3 对关键赖氨酸残基进行 I kappa B α 苏酰化的结果，通常是 K-48 连接的多泛素化所需的。此外，抑制特定的 Sumo 蛋白酶足以从 I kappa B α 中释放 RelA 并激活 NF-kappa B 靶基因。这些结果定义了一条调节 NF-kappa B 激活的新途径，对其在人类健康和疾病中的生理作用很重要。
NF-kappa B activation is a critical component in the transcriptional response to hypoxia. However, the underlying mechanisms that control its activity under these conditions are unknown. Here we report that under hypoxic conditions, I kappa B kinase (IKK) activity is induced through a calcium/calmodulin-dependent kinase 2 (CaMK2)dependent pathway distinct from that for other common inducers of NF-kappa B. This process still requires IKK and the IKK kinase TAK1, like that for inflammatory inducers of NF-kappa B, but the TAK1-associated proteins TAB1 and TAB2 are not essential. IKK complex activation following hypoxia requires Ubc13 but not the recently identified LUBAC (linear ubiquitin chain assembly complex) ubiquitin conjugation system. In contrast to the action of other NF-kappa B inducers, IKK-mediated phosphorylation of I kappa B alpha does not result in its degradation. We show that this results from I kappa B alpha sumoylation by Sumo-2/3 on critical lysine residues, normally required for K-48-linked polyubiquitination. Furthermore, inhibition of specific Sumo proteases is sufficient to release RelA from I kappa B alpha and activate NF-kappa B target genes. These results define a novel pathway regulating NF-kappa Bactivation, important to its physiological role in human health and disease.